Mutagenesis by asbestos in the lung of lambda-lacI transgenic rats

Our plain-English summary of Mutagenesis by asbestos in the lung of lambda-lacI transgenic rats, by J. Topinka, P. Loli, P. Georgiadis, et al (Mutation Research, 2004).

The study

• Authors: J. Topinka, P. Loli, P. Georgiadis, M. Dusinská, M. Hurbánková, Z. Kováciková, K. Volkovová, A. Kazimírová, M. Barancoková, E. Tatrai, D. Oesterle, T. Wolff, S.A. Kyrtopoulos
• Journal: Mutation Research
• Published: 2004;553(1-2):67-78
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

In order to get more insight into the mechanism of asbestos-related lung cancer, the mutagenic potential of asbestos was examined in vivo in rat lung. Groups of five transgenic lambda-lacI (Big Blue) rats were intratracheally instilled with single doses of 1 or 2mg, or with four weekly doses of 2mg, per animal of the amosite asbestos. Sixteen weeks after instillation, the mutation frequency was found to be increased in lung DNA by 2-fold at doses of 2 mg (P = 0.035) and of 4 x 2 mg (P = 0.007) amosite. No significant changes were observed after 4 weeks of exposure. In separate experiments, wild-type F344 rats were treated by the same regimen as described above and markers of inflammation, genotoxicity, cell proliferation and lung tissue damage were analysed. Our results indicate a weak but persistent inflammation and cell proliferation which possibly plays a major role in the observed mutagenic effect.

In plain English

This animal experiment tested whether amosite asbestos causes gene mutations in rat lungs. Groups of five male Big Blue transgenic rats, carrying a gene used to count mutations, had amosite fibres from South Africa placed directly into the windpipe. They received single doses of 1 or 2 mg, or four weekly 2 mg doses. Four weeks after treatment, lung mutation frequency was not significantly increased in any group. Sixteen weeks after treatment, the single 2 mg group had 61.1 mutant plaques per million plaques screened, versus 33.6 in controls (P = 0.035), almost twice as high. The four-dose group had 57.6 versus 35.1 (P = 0.007), which was no further increase. In separate groups of ordinary rats, amosite increased DNA strand breaks in lung cells at both times. Micronuclei in lung macrophages rose significantly only at 16 weeks, but only two animals per group were checked. Inflammatory signalling proteins rose and lung tissue showed inflammation. An oxidative damage marker showed no significant difference from controls. The authors concluded that weak but persistent inflammation and cell proliferation possibly play a major role in the mutations.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment: in vivo mutation assay in transgenic rats, plus separate experiments in wild-type rats measuring toxicity markers
• Who was studied: Male homozygous transgenic lambda-lacI F344 (Big Blue) rats in groups of five, killed 4 or 16 weeks after the last treatment. Male wild-type Fischer 344 rats (groups of 10) were used for strand-break, micronucleus, inflammation and histology measurements. Location and dates of the experiments are not stated.
• Exposure: Amosite (amphibole) asbestos from South Africa, given by intratracheal instillation in saline. Doses were a single 1 mg or 2 mg dose, or four weekly 2 mg doses per animal (wild-type rats: 2 mg or 4 × 2 mg). 75% of fibres were 20 to 30 micrometres long, with an average diameter of 0.71 micrometres. Controls received the vehicle alone.
• Main results:
  • Transgenic rats, 4 weeks after treatment: no significant increase in lung mutation frequency at any dose
  • Mutation frequency was calculated as mutant (blue) phage plaques divided by the total number of plaques, expressed per million (× 10−6)
  • Transgenic rats, 16 weeks after a single 2 mg dose: mutation frequency 61.1 ± 22.9 × 10−6 versus 33.6 ± 8.1 × 10−6 in controls, almost 2-fold higher (P = 0.035)
  • Transgenic rats, 16 weeks after four weekly 2 mg doses: mutation frequency 57.6 ± 12.5 × 10−6 versus 35.1 ± 6.9 × 10−6 in controls (P = 0.007), no further increase over the single 2 mg dose
  • Wild-type rats: DNA single-strand breaks significantly increased (P < 0.001) in lavage macrophages and type II epithelial cells at 2 and 4 × 2 mg, at both 4 and 16 weeks
  • Wild-type rats: micronuclei in alveolar macrophages significantly increased only at 16 weeks. There was no significant increase in type II epithelial cells.
  • Malondialdehyde (oxidative damage marker) in lung tissue of transgenic rats showed no significant difference from controls
  • Wild-type rats: the inflammatory cytokines TNF-alpha and IL-1 were significantly increased about 1.5 to 2.5-fold at both doses and both times
  • Lung tissue of amosite-treated rats showed toxic and structural changes, most evident 16 weeks after treatment
• The authors' conclusion: The authors concluded that weak but persistent inflammation and cell proliferation possibly play a major role in the observed mutagenic effect of amosite in the rat lung.
• Limitations the authors state:
  • Micronucleus results are only indicative because only two animals per group were evaluated
  • The assay detects small gene mutations, so the total mutagenic response may be underestimated
  • Mutations in the few dividing lung cells may be diluted by DNA from more numerous non-dividing cells in the tissue analysed

Topics

Medical terms in this study, explained in our Lexicon: Lung Cancer, Amosite, Inflammation, Genotoxicity.

Related studies

• Benzo[a]pyrene-enhanced mutagenesis by asbestos in the lung of lambda-lacI transgenic rats — P. Loli, J. Topinka, et al. (2004)
• Benzo[a]pyrene-enhanced mutagenesis by man-made mineral fibres in the lung of lamda-lacI transgenic rats — J. Topinka, P. Loli, et al. (2006)
• Chrysotile asbestos fibers mediate homologous recombination in Rat2 lambda fibroblasts: implications for carcinogenesis — K. Lezon-Geyda, C.M. Jaime, et al. (1996)
• Toxicity and mutagenesis of chrysotile asbestos to Agrobacterium radiobacter — N. Yoshida, T. Naka, et al. (2001)
• Genotoxic effects of asbestos in humans — M. Dusinská, A. Collins, et al. (2004)
• On the mechanism of cogenotoxic action between ingested amphibole asbestos fibres and benzo[a]pyrene: I. Urinary and serum mutagenicity studies with rats — C. Varga, G. Horváth, et al. (1998)

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